Human immunodeficiency virus type 1 (HIV-1) enters cells following the interaction of its envelope glycoprotein, gp120, with cell surface receptors. The binding of gp120 to the primary cellular HIV-1 receptor, CD4, induces a conformational change in gp120, which facilitates interaction with members of the chemokine receptor family of cellular proteins. The capacity of HIV-1 to infect different cell types is determined by the chemokine coreceptor partner it uses. So-called ?macrophage tropic? HIV-1 strains utilize the beta chemokine receptor CCR5 whereas HIV-1 isolates, able to replicate in continuous T leukemia cell lines (T-cell line tropic), use the alpha chemokine receptor, CXCR4. Dual-tropic strains of HIV-1 can infect both cell types. Exposed individuals are invariably initially infected with macrophage tropic HIV-1 strains. In approximately 50% of infected persons, the virus evolves into T-cell line tropic strains in vivo, which in general are more pathogenic than the original infecting virus. Dual-tropic virus strains may therefore represent an intermediate or transitional form of HIV-1.HIV-1 viruses were constructed with mosaic gp120 envelopes containing determinants for both macrophage and dual tropism. This permitted us to elucidate the regions of gp120 responsible for the interaction with the CXCR4 coreceptor. Our results indicated that two separate highly variable regions of the HIV-1 envelope glycoprotein (designated V1/V2 and V3) each conferred the capacity of a macrophage tropic virus isolate to switch from using the CCR5 to the CXCR4 coreceptor. This result raised the possibility that these two highly variably regions of HIV-1 gp120 interacted with different extracellular domains of CXCR4. Using chimeric forms of CXCR4 , we showed: 1) dual- tropic gp120 interacts with extracellular domains (E1 and E2) of CXCR4; 2) the V1/V2 and V3 regions of gp120 bind to different regions of CXCR4; and 3) in its interaction with CXCR4, the V1/V2 region of the dual-tropic gp120 plays the dominant role. - HIV-1 envelope glycoprotein, gp120, tropism, chemokine coreceptor, CD4, CXCR4, CCR5, virus entry, fusion